The compound known under the generic name omeprazole is disclosed in EP 0 005 129.
Omeprazole is useful for inhibiting gastric acid secretion and has gastric mucosa protective activity in mammals and man. Omeprazole may be used for prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory diseases in mammals and man, including for example gastritis, gastric ulcer and duodenal ulcer.
Certain salts of omeprazole are disclosed in EP 0 124 495. Canadian patent 2166794 disclosed a form of magnesium omeprazole dihydrate, which has a higher degree of crystallinity. This form has a methanol content of less than 0.1%.
Canadian patent application No. 2254572 discloses a process for the production of magnesium omeprazole crystalline dihydrate.
The S-enantiomer of omeprazole commonly referred as esomeprazole is said to have improved pharmacokinetical properties which give an improved therapeutic profile such as lower degree of inter-individual variation (WO 94/27988). Esomeprazole magnesium, the generic name for magnesium bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole), is a well-known gastric proton-pump inhibitor and has been commercially available from AstraZeneca under the brand name NEXIUM since 2001.
WO 94/27988 describes a solid form of esomeprazole magnesium, WO 95/01977 describes solid omeprazole magnesium with a degree of crystallinity over 70%.
WO 98/54171 describes a magnesium salt of esomeprazole trihydrate characterized by being highly crystalline and stable. It discloses also polymorphic forms (A and B) of esomeprazole magnesium salt dihydrate and processes for their preparation using esomeprazole potassium salt as an intermediate.
WO 04/046134 describes a crystalline esomeprazole magnesium salt trihydrate form II wherein the term trihydrate is used to define a crystalline material in which water molecules are bound in the crystalline lattice. WO 04/089935 provides new polymorphic forms of crystalline esomeprazole magnesium trihydrate, hemihydrate and monohydrate. WO 07/031845 discloses novel polymorphs of esomeprazole magnesium trihydrate (G1 and G2) and processes for their preparation. In addition, a new process for preparing amorphous esomeprazole magnesium is presented. Therefore the preparation of esomeprazole magnesium trihydrate may suffer on repeatability because many forms are possible which could be interchangeable.
Numerous patent applications WO 01/87831, WO 04/037253, WO 04/020436, WO 06/096709, and WO 07/0710753 describe amorphous esomeprazole magnesium with various amounts of water and residual solvents. Again no clear procedure for a unique form can be concluded.
It is generally known that safety and also stability of an active pharmaceutical ingredient depends among other factors strongly upon residual solvents content.
To diminish the effect of residual solvents they should be all removed to the highest possible extend from an active substance.
EP 1 230 237 describes a procedure of removing residual solvents in omeprazole magnesium and EP 1 375 497 a procedure of removing residual solvents in esomeprazole magnesium by flash evaporation but the products have unrepeatable low crystallinity between amorphous and a degree of crystallinity around 25% and still contain various amounts of residual solvents.
The object of the present invention thus was to provide a process for preparing esomeprazole magnesium in a purified and stable form and in repeatable manner even if scaled up, and to correspondingly provide such a purified, stable and reproducible form of esomeprazole magnesium.